Understanding the neurophysiology of reinforcement and craving will improve our ability to develop new medications for the treatment of substance abuse. We have developed procedures for, and have ongoing behavioral studies of, acute cocaine administration and controlled withdrawal which quantify cardiovascular and subjective effects, mood and craving. While there are one or two centers where imaging is carried out following a single cocaine dose, none, to our knowledge, have ever imaged the effects of repeated doses followed by abstinence. Our ability to perform functional imaging on subjects where the administration and withdrawal from cocaine is controlled by the experimenter is an important advantage. We are proposing a five-year study to correlate cocaine's subjective effects with its effects on regional brain activity using dynamic Xenon SPECT, a high-resolution, full-volume, 3-D imaging system which permits quantification of cerebral blood flow at multiple timepoints in a single experiment. Current efforts at medication development are hampered by the lack of markers that would provide early indications of possible effectiveness. We believe that rCBF imaging using high-resolution 133Xenon-SPECT can be developed in carefully designed studies as a marker for drug effects and will ultimately improve treatment outcome. By analyzing time course of pattern changes in brain activity we will shed light on the determinants of cocaine-induced euphoria, reinforcement, dysphoria, and craving. Our center is particularly suited to do this. Specific Aims: 1) Define the initial temporal profile of cerebral activation in acute cocaine administration and a) correlate this profile with subjective experience in a dose-responsive manner using standard subjective effects measures and other observational data; b) confirm that the effect of acute tolerance is to attenuate this activation. 2) Define physiologic markers for the stages of withdrawal and so develop targets for treatment intervention. 3) Demonstrate cerebral activation by cues which elicit craving and a) correlate this activation with self-administration behavior; b) examine the effect of expectation on cue response and the corresponding cerebral activation. Use of these tools, and the data derived from their use, can be of major importance in Medication Development research. They could lead to pharmacological interventions in the treatment of cocaine abuse which could: Prevent cerebral activation by a drug of abuse by modulating receptors; Normalize neurotransmitter activity in the withdrawal state; Diminish relapse likelihood by attenuating the cerebral activation produced by craving.